CN108785256B

CN108785256B - Solid dispersion and preparation method thereof

Info

Publication number: CN108785256B
Application number: CN201810390482.4A
Authority: CN
Inventors: 王立坤; 王伟; 张凤娥; 钱雯
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Chengdu Suncadia Pharmaceuticals Co Ltd
Priority date: 2017-04-28
Filing date: 2018-04-27
Publication date: 2021-06-29
Anticipated expiration: 2038-04-27
Also published as: CN108785256A

Abstract

The invention relates to a solid dispersion and a preparation method thereof. Specifically, the invention relates to a solid dispersion which contains abiraterone or a derivative thereof and a carrier material of hydroxypropyl methyl cellulose acetate succinate, wherein the acetyl substitution (DS) in the hydroxypropyl methyl cellulose acetate succinate_Ac) 0.50 or less and a Degree of Substitution (DS) of the combination of acetyl and succinyl groups_Ac+DS_S) Not less than 0.83, the preparation prepared from the solid dispersion has good dissolution and stability, can eliminate individual difference between patients after taking the medicine, and can eliminate food effect brought by fasting and satiety administration to a certain extent.

Description

Solid dispersion and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a solid dispersion of abiraterone or derivatives thereof, wherein a preparation containing the solid dispersion has good dissolution rate and stability, eliminates individual difference of abiraterone or derivatives thereof in drug reaction, and the like.

Background

Prostate cancer is a common malignant lethal cancer, is the second cause of cancer-related male deaths after lung cancer, and in recent years, the market demand is rapidly increased, and abiraterone acetate is an abiraterone prodrug, is a CYP17 enzyme inhibitor, is approved to be marketed in the United states in 2011, and is suitable for treating prostate cancer patients.

Abiraterone acetate is a lipophilic compound, the octanol-water partition coefficient is 5.12(Log P), the abiraterone acetate is almost insoluble in water, BCS classification belongs to four classes, and therefore, the improvement of the dissolution rate and the bioavailability of the abiraterone acetate is key when the research on the patent medicine is carried out. The solid dispersion is a dispersion system formed by uniformly dispersing a drug in another water-soluble or insoluble or enteric-soluble material in the form of molecules, amorphous or microcrystals and the like. The solid dispersion can improve the dissolution rate and solubility of the insoluble drug, improve the selectivity and stability of the drug and reduce side effects.

CN103813794A discloses a solid dispersion composition of abiraterone analogue or its acceptable salt, wherein the carrier material is a water-soluble polymer, which solves the problem of dissolution of abiraterone analogue after drug formation. CN103070828B also discloses a solid dispersion containing abiraterone acetate and povidone, wherein the mass ratio of the abiraterone acetate to the povidone is 1: 0.5-4, the preparation method of the solid dispersion is complex, and the solid dispersion medicinal preparation does not have good bioavailability.

In the process of treating prostate cancer by abiraterone acetate administration, the problems of large individual difference among patients, large absorption difference of fasting satiety oral drugs and the like exist, and researchers need to deeply research and solve the problems.

Disclosure of Invention

The invention provides a solid dispersion, which contains an active ingredient abiraterone or a derivative thereof and a carrier material hydroxypropyl methyl cellulose acetate succinate (HPMCAS), wherein the acetyl substitution Degree (DS) in the HPMCAS_Ac) 0.50 or less and a Degree of Substitution (DS) of the combination of acetyl and succinyl groups_Ac+DS_S) Not less than 0.83, and the solid dispersion has good dissolution rate and physical stability.

In embodiments, the degree of substitution of acetyl groups in the carrier material hydroxypropylmethylcellulose acetate succinate (DS) in the solid dispersion_Ac) 0.50 or less, Degree of Substitution (DS) of acetyl and succinyl groups_Ac+DS_S) Not less than 0.85 and (DS)_Ac+DS_S) Less than or equal to 0.92. In othersIn embodiments, the degree of substitution of acetyl groups in the carrier material hydroxypropylmethylcellulose acetate succinate (DS) in the solid dispersion_Ac) 0.50 or less, Degree of Substitution (DS) of acetyl and succinyl groups_Ac+DS_S) Not less than 0.85 and (DS)_Ac+DS_S) Is less than or equal to 0.89, and compared with a non-solid dispersion, the dissolution rate of the abiraterone or the derivatives thereof can be improved by at least 4 times, and can be 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 45, 50, 55 and 60 times.

Further, the degree of substitution of acetyl (DSAc) in hydroxypropyl methylcellulose acetate succinate as a carrier material in the solid dispersion is more than or equal to 0.44, and less than or equal to 0.49 of (DSAc), more than or equal to 0.39 of succinyl (DSS), and less than or equal to 0.43 of (DSS), and the degree of substitution of the combination of acetyl and succinyl (DSAc + DSS) is more than or equal to 0.85, and less than or equal to 0.89 of (DSAc + DSS), compared with a non-solid dispersion, the solid dispersion can improve the dissolution rate of the abiraterone or the derivative thereof by more than at least 4 times, and can be 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 45, 50, 55 and 60 times.

In an embodiment, the solid dispersion of the present invention has a weight ratio of the carrier material to the active ingredient of at least 0.5:1, which can change the crystalline state of the active ingredient to amorphous state, improve the absorption of the drug, and make the drug have fast onset of action after oral administration, high bioavailability, and is beneficial for preparing a high dosage formulation, and the solid dispersion itself is stable.

The higher the content of carrier material in the present invention, the easier it is to change the active ingredient from crystalline to amorphous, and the higher the bioavailability of the corresponding solid dispersion. In view of the balance between drug loading and bioavailability, the weight ratio of carrier material to active ingredient or derivative thereof in the present invention may be 0.5:1 to 5:1, preferably 1:1 to 4:1, and in some embodiments may be 1:1, 1.2:1, 1.5:1, 1.7:1, 2:1, 2.3:1, 2.5:1, 2.8:1, 3:1, 3.3:1, 3.5:1, 3.8:1, 4: 1.

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is a substituted cellulosic polymer, by "substituted cellulosic polymer" is meant a polymer which passes through the sugar repeating unitsA cellulosic polymer modified by the reaction of at least a portion of the hydroxyl groups with a compound to form ester-linked or ether-linked substituents. The skilled person finds that it has a high degree of substitution by acetyl groups (DS)_Ac) The HPMCAS polymer of (a) provides more hydrophobic groups, resulting in increased solubility of the low solubility active substance in the polymer, while allowing the polymer to be dissolved or dispersed in water at a pH of 5-8. Relative to the higher degree of acetyl substitution (DS)_Ac) The HPMCAS polymer has higher succinyl substitution Degree (DS)_S) The HPMCAS polymer of (a) enables faster release of the pharmaceutical formulation in vivo.

The degree of substitution of hydroxypropoxy, methoxy, acetyl and succinyl groups on the polymer can be determined from the weight percent of substituents on the polymer, which can be determined using methods well known in the art. See, for example, US4226981 and Japanese Pharmaceutical Excipients (1993, page 182-187), the disclosures of which are incorporated herein by reference.

Backbone (wt%) -100-methoxy (wt%) -hydroxypropoxy (wt%) -acetyl (wt%) -succinyl (w%)

(4)

The hydroxypropyl methylcellulose acetate succinate (HPMCAS) of the present invention may be a Shin-Etsu HPMCAS polymer hydroxypropyl methylcellulose acetate succinate having the following substituent levels, as shown in table 1:

TABLE 1

Note: DS (direct sequence)_MDegree of substitution of methoxy; DS (direct sequence)_HPDegree of substitution of hydroxypropoxyl; DS (direct sequence)_ACDegree of substitution of acetyl; DS (direct sequence)_SDegree of substitution of succinyl.

Examples of the method for producing the solid dispersion include a melting method, a solvent method, and a solvent-melting method. Other methods utilize the co-dissolution principle, a eutectic mixture is formed by a grinding method, and the medicine is dissolved in an organic solvent and is dispersed and adsorbed on an inert material to form a solid surface adsorbate.

The solvent method (also called coprecipitation method) is to dissolve the drug and the carrier in an organic solvent together or uniformly mix the drug and the carrier after dissolving the drug and the carrier in the solvent, or to suspend and disperse the carrier material in the organic solvent of the active ingredient or the pharmaceutically acceptable salt thereof, and then to remove the solvent to obtain the solid dispersion. The method for removing the solvent is known to or can be determined by a person skilled in the art, and can be a mode of dripping the high-polarity organic solvent into the low-polarity solvent to precipitate a solid; spray drying or reduced pressure drying may be used.

The melting method is that the medicine and the carrier are mixed evenly and heated to be molten, or the carrier is heated to be molten, then the medicine is added and stirred to be dissolved, and then the melt is rapidly cooled to be solid under violent stirring or is directly filled into a capsule and then cooled.

The solvent-melting method is to dissolve the medicine with a small amount of organic solvent and then mix the dissolved medicine with the melted carrier uniformly, evaporate the organic solvent, and cool and solidify the medicine.

In a preferred embodiment, the solid dispersion of the present invention is prepared by a melting method, which is also called a hot-melt extrusion method, that is, the drug and the carrier are mixed and heated to be molten, or the carrier is heated to be molten, then the drug is added to be stirred and dissolved, and then the melt is rapidly cooled to be solid under vigorous stirring or directly filled into a capsule and then cooled. Compared with other methods, the solid dispersion of the abiraterone or the derivative thereof obtained by the melting method has the advantages inherent in the method and the advantages peculiar to the solid dispersion of the abiraterone or the derivative thereof, such as very stable extruded samples under accelerated stability conditions, high bioavailability and the like.

In some embodiments, the solid dispersion is made using a twin screw hot melt extruder comprising: 1) pulverizing abiraterone or its derivatives and carrier material, respectively, and mixing; 2) and (2) crushing the mixture obtained in the step 1) after hot-melt extrusion by a double-screw hot-melt extruder. Further, the step 1) further comprises a sieving step, wherein the sieving mesh is 40-100 meshes, and in an embodiment, the sieving mesh can be 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 meshes.

Further, the hot-melt extrusion temperature affects the stability of the solid dispersion and the content of related substances, and the hot-melt extrusion temperature is preset to be 120-145 ℃, so that the contact time of the abiraterone or the derivative thereof with heat is reduced, and the abiraterone or the derivative thereof is prevented from being degraded due to overhigh temperature, and the hot-melt extrusion temperature can be 120 ℃, 122 ℃, 124 ℃, 126 ℃, 128 ℃, 130 ℃, 132 ℃, 134 ℃, 136 ℃, 138 ℃, 140 ℃, 142 ℃, 145 ℃ and preferably 130-135 ℃.

The solid dispersion of the invention can be further prepared into a solid preparation which is selected from but not limited to tablets, pills, granules or capsules.

Wherein the solid preparation further comprises a pharmaceutically acceptable excipient which is well known or can be determined by the technical personnel in the field and is selected from at least one of but not limited to a disintegrant, a filler, a binder and a lubricant. The solid preparation has the advantages of rapid and complete dissolution, good bioavailability, simple preparation process, and suitability for process amplification.

The present invention also provides a method for preparing the above solid preparation, which comprises: firstly, crushing the solid dispersion, then uniformly mixing the solid dispersion with excipients such as a filling agent and/or a disintegrating agent required by solid preparation forming, adding an adhesive for wet granulation or dry granulation, drying, sieving, granulating, uniformly mixing with a lubricant, and preparing pills or granules or tabletting or capsules; or directly encapsulating or tabletting with solid dispersion and adjuvant; the granules, tablets or capsules may be further coated as required.

In an embodiment, the method of preparing a solid formulation comprises: 1) mixing abiraterone or a derivative thereof with a carrier material, 2) then carrying out hot-melt extrusion and crushing on the mixture obtained in the step 1), and 3) mixing the obtained solid dispersion with at least one excipient selected from a disintegrating agent, a filling agent, a binding agent and a lubricating agent.

In an embodiment, the hot melt extrusion is performed using a twin screw hot melt extruder, and the hot melt extrusion temperature is preset to 120 to 145 ℃, and may be 120 ℃, 122 ℃, 124 ℃, 126 ℃, 128 ℃, 130 ℃, 132 ℃, 134 ℃, 136 ℃, 138 ℃, 140 ℃, 142 ℃, 145 ℃, and preferably 130 to 135 ℃.

The preparation method of the solid preparation comprises the following steps:

1) respectively pulverizing abiraterone acetate and carrier material, sieving, and mixing;

2) the extrusion temperature of the double-screw hot-melt extruder is preset to be 120-145 ℃, the screw is started after the preset temperature is reached, and then the mixture obtained in the step 1) is added into the extruder and extruded by the screw;

3) crushing and sieving the solid obtained in the step 2) to obtain a solid dispersion;

further, the mesh sieved in the step 3) is 40-100 meshes.

The dosage numerical range of the active ingredients or other types of pharmaceutical excipients is calculated by the weight of the tablet core without the coating agent according to the weight of the solid preparation, and the specific reference can be made in the examples.

The abiraterone derivative is a compound which is formed by abiraterone and acyl, alkyl and other groups into an ester or ether structure, and can be metabolized into the abiraterone in vivo, wherein the abiraterone derivative is selected from, but not limited to, abiraterone acetate.

The 'purification' or 'content' is obtained by HPLC detection, and the HPLC detection conditions are as follows: octadecylsilane chemically bonded silica is used as a filler (Agilent poroshell120EC-C18, 3.0mm multiplied by 50mm, 2.7 mu m); and (3) taking ammonium acetate and/or acetonitrile as a mobile phase, eluting, and detecting at 254 nm.

The pharmaceutical excipients or reagents of the invention are all commercially available, for example, hydroxypropyl methylcellulose acetate succinate is commercially available from Shin-Etsu company; and abiraterone acetate: (3 β) -17- (3-pyridyl) androsta-5, 16-dien-3-ol acetate, abiraterone: (3 beta) -17- (3-pyridyl) androst-5, 16-dien-3-ol can be prepared as described in the example of CN 101528308.

Drawings

FIG. 1: bulk drug substance abiraterone acetate, HMPCAS HG, abiraterone acetate with HMPCAS HG and control of X-ray diagram of experimental example 4 solid dispersion.

Detailed Description

The present invention is further illustrated in detail by the following examples and experimental examples. These experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: preparation of solid dispersions

The solid dispersion is prepared by mixing the compound A and different carrier materials, and the specific formula is shown in the following table 2:

TABLE 2

The preparation method comprises the following steps:

1) respectively sieving the abiraterone acetate and the carrier material by a 40-80-mesh sieve, respectively weighing the abiraterone acetate and the carrier material according to the weight percentage of 1:3, and fully and uniformly mixing;

2) presetting the extrusion temperature of each heating area of a double-screw hot-melt extruder 1-8 to be 120-145 ℃, starting a screw to slowly add the mixture obtained in the step 1) into the extruder from a feeding hopper when the preset temperature is reached, and carrying out hot-melt extrusion at the rotating speed of 150-300 RPM;

3) crushing the solid extrudate obtained in the step 2), and sieving the crushed solid extrudate with a 60-100-mesh sieve to obtain a solid dispersion with uniform particles.

Example 2

The solid dispersion was prepared by mixing compound a with different kinds of carrier materials, and the specific formulation is shown in table 3:

TABLE 3

The preparation method comprises the following steps:

dissolving abiraterone acetate and a carrier material in a dichloromethane/methanol mixed solvent, fully and uniformly stirring according to the proportion in the table 3, preparing a solution, performing spray drying by using spray drying equipment, and drying a spray-dried product by using a vacuum drying oven to obtain the abiraterone acetate amorphous solid dispersion.

Example 3

The solid dispersion was prepared by mixing compound a with different kinds of carrier materials, and the specific formulation is shown in table 4:

TABLE 4

The preparation method comprises the following steps:

dissolving abiraterone acetate and a carrier material into a dichloromethane/methanol mixed solvent together, evaporating the organic solvent to separate out the drug and the carrier material simultaneously to obtain a coprecipitate formed by mixing the abiraterone acetate and the carrier material, and drying to obtain the abiraterone acetate solid dispersion.

Appearance and yield

The appearance and recovery data of the solid dispersions of examples 1 to 3 and comparative examples 1 to 6 were compared.

TABLE 5

Composition (I)	Appearance of the product	Recovery (%)
			Experimental example 1	Dry dispersion	82
Experimental example 2	Dry dispersion	80
			Experimental example 3	Dry dispersion	79
Comparative example 1	High viscosity and moistening	53
			Comparative example 2	High viscosity and moistening	49
Comparative example 3	High viscosity and moistening	61
			Comparative example 4	Coarse particles and high viscosity	42
Comparative example 5	Coarse particles and high viscosity	44
			Comparative example 6	Coarse particles and high viscosity	38

The results show that: the abiraterone acetate solid dispersion prepared by hot-melt extrusion is not agglomerated, the agglomeration phenomenon is obviously lower than that of the solid dispersion prepared by spray drying and coprecipitation methods, the granularity of a sample obtained by the coprecipitation method is large, and in addition, the yield of the hot-melt extrusion is also higher than that of the spray drying and coprecipitation methods, but the requirements for preparing the solid dispersion can be met.

Flowability of powder

The angle of repose is measured in a state of rest when the particles are in equilibrium with gravity applied thereto and the friction between the particles when sliding on the free inclined surface of the powder accumulation layer, and therefore the smaller the angle of repose, the smaller the friction force, and the better the flowability. The angle of repose was determined for the solid dispersion powders of examples 1 to 3 and comparative examples 1 to 6 according to national standard GB 11986-89, "measurement of angle of repose for surfactant, powder and particles".

TABLE 6

The results show that: the flowability of the abiraterone acetate solid dispersion prepared by hot-melt extrusion is superior to that of the solid dispersion prepared by spray drying and coprecipitation methods, but the requirement for preparing the solid dispersion can be met.

Example 4

The preparation method comprises the following steps:

(1) respectively crushing the abiraterone acetate and the polymer, sieving the crushed abiraterone acetate and the polymer by a sieve with 40-80 meshes, and uniformly mixing the crushed abiraterone acetate and the polymer according to the weight percentage of 1:3 to prepare a physical mixture.

(2) Setting the extrusion temperature of a double-screw hot-melt extruder to be 120-145 ℃, starting a screw when the preset temperature is reached, adding the physical mixture obtained in the step 1) into the extruder, and extruding a strip-shaped object through the screw;

(3) crushing the strips in the step 2), and sieving the crushed strips with a 60-100-mesh sieve to obtain solid dispersion powder with uniform granularity.

TABLE 7

Dissolution test

According to the second method (paddle method) of dissolution determination of the Chinese pharmacopoeia 2015 edition, the dissolution determination is carried out on the abiraterone acetate amorphous solid dispersion powder obtained in the experimental examples 1-4, 6-8 and the bulk drug with the same dosage. The pharmaceutical composition of the present invention was dissolved in 300mL FaSSGF (medium simulating fasting gastric juice) solution at pH 1.6 for 15min, and FaSSIF (medium simulating fasting intestinal juice) solution was added to 900mL (pH 6.5 was adjusted), and dissolution test was performed at 37 ± 0.5 ℃ and 50 rpm.

TABLE 8

Note: a is not prepared as a solid dispersion

From the results, the dissolution of HPMCAS MG, HPMCAS LG, Soluplus, PVP VA64 and ewing L100-55 in physiologically relevant media was improved compared to the drug substance, with the best effect of ewing L100-55, HPMCAS LG and HPMCAS MG. HPMC E5LV was not tested because it could not be extruded below 145 ℃, it could not be prepared as a solid dispersion with abiraterone, and extrusion could not be completed even if the temperature was raised above 200 ℃.

Detection of related substances

The solid dispersion powders obtained in Experimental examples 1, 2, 3, 4, 6, 7 and 8 were left at 40 ℃ and 75% humidity to examine the stability of the solid dispersion for 30 days, and the substances were measured by HPLC, as shown in Table 9.

TABLE 9

From the results, under the conditions of 40 ℃ and 75% humidity, the impurity conditions of samples of the abiraterone acetate solid dispersion are greatly different after being placed for 30 days, wherein the impurity growth of the samples of the HPMC AS series is not obvious, and the impurity growth rate of the solid dispersion prepared by other carrier materials is high and does not meet the impurity limit established by the ICH guide principle. For example, the solid dispersion prepared by the Eudragit L100-55 has good dissolution effect, but the impurities grow rapidly when the solid dispersion is placed under the conditions of 40 ℃ and 75% humidity, and the quality standard of the later preparation can not be met at all. Further, in the HPMC AS series, the HPMC AS LG solid dispersion exhibited both excellent dissolution and excellent stability.

Claims

1. A solid dispersion comprising the active ingredient abiraterone, or a salt thereof, and a carrier material hydroxypropyl methylcellulose acetate succinate (HPMCAS), characterised in that the acetyl Degree of Substitution (DS) in the hydroxypropyl methylcellulose acetate succinate_Ac) Not less than 0.44 and (DS)_Ac) Less than or equal to 0.49, Degree of Substitution (DS) of succinyl_S) Not less than 0.39 and (DS)_S) 0.43 or less, Degree of Substitution (DS) of combination of acetyl and succinyl groups_Ac+DS_S) Not less than 0.85 and (DS)_Ac+DS_S)≤0.89。

2. The solid dispersion according to claim 1, characterized in that the weight ratio of the carrier material to the active ingredient is 0.5:1 to 5: 1.

3. The solid dispersion according to claim 1, characterized in that the weight ratio of the carrier material to the active ingredient is from 1:1 to 4: 1.

4. The solid dispersion according to any one of claims 1 to 3, characterized in that it consists of abiraterone or a salt thereof, and a carrier material.

5. A solid dispersion according to any one of claims 1 to 3, characterized in that the salt of abiraterone is abiraterone acetate.

6. The solid dispersion according to claim 4, characterized in that the salt of abiraterone is abiraterone acetate.

7. The solid dispersion according to any one of claims 1 to 3 or 6, wherein the solid dispersion is produced by a hot-melt extrusion method.

8. The solid dispersion according to claim 4, characterized in that it is prepared by hot-melt extrusion.

9. The solid dispersion according to claim 5, characterized in that it is prepared by hot-melt extrusion.

10. A solid formulation comprising the solid dispersion of any one of claims 1-3, 6, 8-9, said solid formulation selected from a tablet, a pill, a granule, or a capsule.

11. A solid formulation comprising the solid dispersion of claim 4, selected from a tablet, a pill, a granule, or a capsule.

12. A solid formulation comprising the solid dispersion of claim 5, selected from a tablet, a pill, a granule, or a capsule.

13. A solid formulation comprising the solid dispersion of claim 7, selected from a tablet, a pill, a granule, or a capsule.

14. The solid preparation according to claim 10, wherein the solid preparation further comprises a pharmaceutically acceptable excipient selected from at least one of a disintegrant, a filler, a binder, and a lubricant.

15. The solid preparation according to any one of claims 11 to 13, characterized in that the solid preparation further comprises a pharmaceutically acceptable excipient selected from at least one of a disintegrant, a filler, a binder, and a lubricant.

16. A method of preparing the solid formulation of claim 14, comprising: 1) mixing abiraterone or a salt thereof with a carrier material, 2) then carrying out hot-melt extrusion and crushing on the mixture obtained in the step 1), and 3) mixing the obtained solid dispersion with at least one excipient selected from a disintegrating agent, a filling agent, a binding agent and a lubricating agent.

17. A method of preparing the solid formulation of claim 15, comprising: 1) mixing abiraterone or a salt thereof with a carrier material, 2) then carrying out hot-melt extrusion and crushing on the mixture obtained in the step 1), and 3) mixing the obtained solid dispersion with at least one excipient selected from a disintegrating agent, a filling agent, a binding agent and a lubricating agent.